Project Summary/Abstract Studies from our laboratory over the past decade have found the existence of a novel light-dependent insulin receptor (IR) signaling pathway in rod photoreceptors. We have discovered that IR activation is functionally important for rod survival, since its deletion in rods resulted in the loss of neuroprotective survival signaling. This novel pathway uses growth factor receptor bound protein (Grb14), an upstream regulator of IR, and requires photobleaching of rhodopsin for membrane targeting. Grb14 protects light-dependent IR activation in rod photoreceptors against dephosphorylation by PTP1B. Light-activated IR is subsequently associated with phosphoinositide 3-kinase (PI3K), a cell survival factor, and thus regulates the downstream survival pathway. These studies suggest that rhodopsin photoexcitation may trigger signaling events alternative to the classical transducin activation. Recently, it was suggested that the IR signaling pathway is important for cone photoreceptor survival in retinitis pigmentosa (RP) models since systemic administration of insulin delays the death of cone photoreceptors. We found that insulin-like growth factor-1 receptor (IGF-1R) also activates PI3K and Akt survival pathway in rods under light stress. It is our hypothesis that IR/IGF-1R signaling pathways are important for survival and maintenance of rod and cone photoreceptor structure and function. The long-term goal of our project is to gain a greater understanding of the intracellular signaling pathways that provide neuroprotection to both rod and cone photoreceptor cells. The specific objective is to investigate the role of IR and IGF-1R in the regulation of photoreceptor structure and function. To this end, we will determine the mechanism by which Grb14 activates the IR and determine the functional roles of IR and IGF-1R in both rod and cone photoreceptor cells. We will utilize a combination of genetic, molecular, and biochemical approaches to address our specific aims. Results from these studies will lead to a better understanding the roles of IR and IGF-1R signaling in photoreceptor structure, function and survival.